American Society of Hematology

$Mitochondrial mutations further delineate the subclonal structure. (A) Mitochondrial DNA (mtDNA) mutations detected in scATAC-seq data across patients. Only mtDNA mutations with a mean heteroplasmy >1% in at least one of the paired samples were considered. The color bar at the top indicates the respective patient and sampling time point before treatment (T1) and at relapse (T2). (B) Inferred phylogenetic clonal tree for patient RRMM15. Top node denotes the common ancestor, from which subclones are derived according to their respective CNA and mtDNA mutation changes detected via WGS, scRNA-seq, and scATAC-seq. (Bottom) scATAC-seq heatmap of 1912 differential accessibility peaks and 3034 differential gene scores across subclones for patient RRMM15. Color indicates the column Z score of normalized peak accessibility and gene scores, respectively. (C) Heatmap of mtDNA mutations inferred from scATAC-seq data across subclones for patient RRMM15. Only mtDNA mutations with a mean heteroplasmy >1% in at least one of the 2 samples are shown. The proportion of cells per mtDNA mutation, subclone, and time point is shown. Clonal relationships are indicated by framing branches. Color legend indicates the heteroplasmy of mtDNA mutations. (D-E) UMAP plots of single RRMM cells clustered according to chromatin accessibility profiles for patient RRMM15. Examples for (D) subclone enriched and (E) branch enriched mtDNA mutations are shown. Each individual cell is colored according to (top) the respective subclone or (bottom) the heteroplasmy of the indicated mtDNA mutations, with red representing >10% and gray, 0%. (F) Heatmap of the most highly variable 72 TF motifs across all subclones of T1 and T2. Color indicates pseudobulk TF motif deviation score per subclone. (G) UMAP plots of single RRMM cells. Each cell is colored according to the TF motif deviation score of POU5F1B, TCF3, and IRF4. (H) Stability of mtDNA mutations from diagnosis to relapsed/refractory disease. Line plots showing the variant allele frequency of each mtDNA mutation in longitudinal samples of the indicated patients. Only mtDNA mutations with a mean heteroplasmy >1% in at least 1 of the paired samples (T1/T2) were considered. mtDNA mutations enriched in relapsed/refractory samples are colored in red.$

Mitochondrial mutations further delineate the subclonal structure. (A) Mitochondrial DNA (mtDNA) mutations detected in scATAC-seq data across patients. Only mtDNA mutations with a mean heteroplasmy >1% in at least one of the paired samples were considered. The color bar at the top indicates the respective patient and sampling time point before treatment (T1) and at relapse (T2). (B) Inferred phylogenetic clonal tree for patient RRMM15. Top node denotes the common ancestor, from which subclones are derived according to their respective CNA and mtDNA mutation changes detected via WGS, scRNA-seq, and scATAC-seq. (Bottom) scATAC-seq heatmap of 1912 differential accessibility peaks and 3034 differential gene scores across subclones for patient RRMM15. Color indicates the column Z score of normalized peak accessibility and gene scores, respectively. (C) Heatmap of mtDNA mutations inferred from scATAC-seq data across subclones for patient RRMM15. Only mtDNA mutations with a mean heteroplasmy >1% in at least one of the 2 samples are shown. The proportion of cells per mtDNA mutation, subclone, and time point is shown. Clonal relationships are indicated by framing branches. Color legend indicates the heteroplasmy of mtDNA mutations. (D-E) UMAP plots of single RRMM cells clustered according to chromatin accessibility profiles for patient RRMM15. Examples for (D) subclone enriched and (E) branch enriched mtDNA mutations are shown. Each individual cell is colored according to (top) the respective subclone or (bottom) the heteroplasmy of the indicated mtDNA mutations, with red representing >10% and gray, 0%. (F) Heatmap of the most highly variable 72 TF motifs across all subclones of T1 and T2. Color indicates pseudobulk TF motif deviation score per subclone. (G) UMAP plots of single RRMM cells. Each cell is colored according to the TF motif deviation score of POU5F1B, TCF3, and IRF4. (H) Stability of mtDNA mutations from diagnosis to relapsed/refractory disease. Line plots showing the variant allele frequency of each mtDNA mutation in longitudinal samples of the indicated patients. Only mtDNA mutations with a mean heteroplasmy >1% in at least 1 of the paired samples (T1/T2) were considered. mtDNA mutations enriched in relapsed/refractory samples are colored in red.

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